Early Growth Response Gene-1and Its Related Signaling Regulate Blood Glucose Homeostasis

The maintenance of blood glucose homeostasis is important for the organs to function well. The imbalance of blood glucose homeostasis can lead to the damage of these organs. It is insulin and glucagon that are responsible for the blood glucose homeostasis. The abnormal responsiveness of these organs to the hormones leads to imbalance of blood glucose homeostasis such as diabetes. Insulin resistance and hyperglucagonemia are the main cause of the diabetes, however, the detailed mechanisms are still in debate.We started our study with the early growth response gene-1and identified one of its target genes, geranylgeranyl biphosphate synthase (GGPPS), by Chromatin Immunoprecipitation (ChIP) and Electrophoretic mobility shift assay (EMSA). GGPPS can promote the prenylation and cell membrane binding of Ras and Ras related small G proteins with activating MAPK signaling by producing GGPP. The constant stimulation can alter the response of cell by activating Egr-1/GGPPS/MAPK continuously.Next, we studied the role of Egr-1and its target gene GGPPS in insulin signaling pathway. We found that Egr-1/GGPPS could promote prenylation of Ras and activate Ras/MAPK/Erkl/2on the cell membrane under hyperinsulinism.The activated MAPK/Erkl/2inhibited the PI3K/AKT through phosphating the612serine of IRS-1. In this way, Egr-1/GGPPS led to adipocytes insulin resistance. Disruption of this signaling can alleviate the adipocytes insulin resistance. This indicates that Egr-1/GGPPS/MAPK is a negative feedback pathway in insulin signaling.Then, we further hypothesized that Egr-1/GGPPS/MAPK is involved in regulating blood glucose homeostasis. Liver, as one central organ for glucose homeostasis, can respond to both insulin and glucagon with their receptors. To make a better understanding of glucose homeostasis, we studied the mechanisms of liver responding to both hormones under fed or fasting status. We found that hepatic Egr-1and GGPPS can both respond to insulin, whereas the expression of hepatic GGPPS was dependent on Egr-1. Egr-1/GGPPS/MAPK regulated hepatocytes insulin signaling in a negative feedback way, in case of insulin overreacting in hepatocytes in postprandial.Egr-1could enhance hepatic gluconeogenesis responding to glucagon in fasting status. Another target gene of Egr-1, C/EBPa was identified and proved to enhance glucagon induced hepatic gluconeogenesis in a positive feedback way. Notably, early intervention of Egr-1expression level alleviated the symptom of type2diabetes in mice.Taken together, Egr-1is a key transcription factor for regulating blood glucose homeostasis responding to insulin and glucagon in postprandial and fasting status, respectively. It suggests that the abnormal expression of Egr-1may be the primary cause of type2diabetes. This study not only provides an excellent way to get a better understanding of blood glucose homeostasis, but also indicates a good target for treating type2diabetes.